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| United States Patent |
5,182,097
|
|
Byron
, et al.
|
January 26, 1993
|
Formulations for delivery of drugs by metered dose inhalers with reduced
or no chlorofluorocarbon content
Abstract
Aerosol formulations for use in metered dose inhalers are disclosed which
include 1,1,1,2-tetrafluoroethane alone and in combination with other
compounds as well as various hydrocarbon blends. The density, vapor
pressure, flame extension characteristics, dispersability of medicant,
dissolvability of surfactant, respirable fraction, and compatibility
elastomer seals for the aerosol formulations have been examined. The
aerosol formulations are attractive alternatives to chlorofluorocarbon
based aerosols since they do not deplete the ozone layer.
| Inventors:
|
Byron; Peter R. (Richmond, VA);
Dalby; Richard N. (Richmond, VA)
|
| Assignee:
|
Virginia Commonwealth University (Richmond, VA)
|
| Appl. No.:
|
655668 |
| Filed:
|
February 14, 1991 |
| Current U.S. Class: |
424/45; 514/653; 514/784; 514/970 |
| Intern'l Class: |
A61K 009/12; A61K 031/135; C07C 019/08 |
| Field of Search: |
424/47,45
570/170
128/203.15,200.23
|
References Cited
U.S. Patent Documents
| 3644353 | Feb., 1972 | Lunts et al. | 564/150.
|
| 4254129 | Mar., 1981 | Carr et al. | 424/267.
|
| 4254130 | Mar., 1981 | Carr et al. | 424/267.
|
| 4285957 | Aug., 1981 | Carr et al. | 424/267.
|
| 4285958 | Aug., 1981 | Carr et al. | 424/267.
|
| 4311863 | Jan., 1982 | Gumprecht | 570/170.
|
| 4584387 | Jan., 1990 | Butina et al. | 514/415.
|
| 4686099 | Jul., 1987 | Palinczar | 424/47.
|
| 4778674 | Oct., 1988 | Gupte et al. | 424/45.
|
| 5006568 | Apr., 1991 | Fukazawa et al. | 521/98.
|
| 5126123 | Jun., 1992 | Johnson | 424/45.
|
| Foreign Patent Documents |
| 0372777 | Nov., 1989 | EP.
| |
Other References
Dalby & Bryon, "Comparison of Output Particle Size Distributions from
Pressurized Aerosols Formulated as Solutions and Suspensions", Pharm. Res.
5, 36-39 (1988).
British Pharmacopoeia, p. 875, Appendix XVIIC, A204-A207 (1988).
Dalby et al., CFC Propellant Substitution: P-134a as a Potential
Replacement for P-12 in MDI's Pharmaceutical Technology, Mar. 1990.
Nelson et al., Alternative Formulations to Reduce CFC use in U.S. EPA
Contract No. 68-02-4286.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Levy; Neil
Attorney, Agent or Firm: Whitham & Marhoefer
Claims
Having thus described our invention, what we claim as new and desire to
secure by Letters Patent is as follows:
1. An aerosol formulation for use in delivering medication to a patient via
an inhalation device, comprising:
a propellant consisting solely of 1,1,1,2-tetrafluoroethane, said
propellant comprising at least 90% by weight of said aerosol formulation;
an inhalable medicant dispersed or dissolved in said propellant, said
inhalable medicant having a particle size less than 100 microns in
diameter, said inhalable medicant comprising no more than 5% by weight of
said aerosol formulation; and
oleic acid employed as a surfactant for aiding in dispersing said inhalable
medicant in said propellant, said oleic acid comprising no more than 0.2%
weight in volume of said aerosol formulation.
2. An aerosol formulation as recited in claim 1 wherein said inhalable
medicant is albuterol.
3. An aerosol formulation for use in delivering medication to a patient via
an inhalation device, comprising:
a propellant blend comprising at least two different hydrocarbon compounds
and having a vapor pressure ranging between 17 and 108 pounds per square
inch gauge, said propellant blend comprising at least 90% by weight of
said aerosol formulation;
an inhalable medicant dispersed or dissolved in said propellant blend, said
vapor pressure of said propellant blend being sufficient to produce a fine
mist of said inhalable medicant, said inhalable medicant having a particle
size less than 100 microns in diameter, said inhalable medicant comprising
no more than 5% by weight of said aerosol formulation; and
an amount of oleic acid for aiding in dispersing said inhalable medicant in
said propellant blend, said amount comprising no more than 0.2% weight in
volume of said aerosol formulation.
4. An aerosol formulation as recited in claim 3 wherein said inhalable
medicant is albuterol.
5. An aerosol formulation as recited in claim 3 wherein said vapor pressure
of said propellant blend ranges from 40 to 90 pounds per square inch
gauge.
6. An aerosol formulation as recited in claim 3 wherein at least one of
said hydrocarbon compounds is selected from the group consisting of
propane, n-butane, and isobutane.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to propellant compositions used for
delivering drugs to patients from metered dose inhalers and, more
particularly, to propellant compositions which have reduced or no
chlorofluorocarbon content such that their use is environmentally sound.
2. Description of the Prior Art
Metered dose inhalers (MDIs) are, at present, the most efficient and
best-accepted means for accurately delivering drugs in small doses to the
human respiratory tract. Therapeutic agents commonly delivered by the
inhalation route include bronchodilators (B2 agonists and
anticholinergics), corticosteroids, and anti-allergics. Inhalation may
also be a viable route for anti-infective, vaccinating, systemically
acting and diagnostic agents, as well as anti-leukotrienes, and
anti-proteases.
MDIs comprise a pressure resistant container typically filled with a
product such as a drug dissolved in a liquified propellant or micronized
particles suspended in a liquified propellant where the container is
fitted with a metering valve. Actuation of the metering valve allows a
small portion of the spray product to be released whereby the pressure of
the liquified propellant carries the dissolved or micronized drug
particles out of the container to the patient. The valve actuator is used
to direct the aerosol spray into the patient's oropharynx. Surfactants are
usually dissolved in the spray product and can serve the dual functions of
lubricating the valve and reducing aggregation of micronized particles.
For many years the preferred propellants used in MDIs were a group of
chlorofluorocarbons which are commonly called Freons or CFCs, such as
CCl.sub.3 F (Freon 11 or CFC-11), CCl.sub.2 F.sub.2 (Freon 12 or CFC-12),
and CClF.sub.2 -CClF.sub.2 (Freon 114 or CFC-114). Often times the
propellant used in the MDI is a blend of compounds and the combination of
Freon 11, Freon 12, and Freon 114 has been in widespread use in the MDI
industry for many years. Chlorofluorocarbons have qualities particularly
suitable for use in MDIs including vapor pressures, densities, and
elastomer swelling properties which provide respectively for optimal
respirable fractions, enhanced suspension stability, and repeatable valve
metering.
Recently, however, the use of chlorofluorocarbons per se has come under
sharp attack because they are known to deplete stratospheric ozone. Hence,
chlorofluorocarbons are considered to be extremely hazardous to the
environment. Signatory countries to the Montreal Protocol on Substances
that Deplete the Ozone Layer, have resolved to reduce the use of
chlorofluorocarbons in a step-by-step fashion over the next ten years and
ban their use altogether after the year 2000 a.d. No exemption has been
made in the Montreal Protocol for the use of chlorofluorocarbons in MDIs.
Therefore, identification of any alternative propellant system(s) which
can be used in MDIs will provide an immediate benefit to the MDI industry,
and the patients they serve.
Suitable propellant systems may be found in a large number of different
classes of halogenated and non-halogenated hydrocarbons including:
hydrochlorofluorocarbons (HCFCs) which are alkyl molecules with chloro,
fluoro, and hydrogen moieties on the carbon backbone; hydrofluorocarbons
(HFCs) which are alkyl molecules with fluoro and hydrogen moieties on the
carbon backbone; hydrocarbons (HCs) which include alkane and alkene
molecules having only hydrogen moieties on the carbon backbone;
fluorocarbons (FCs) which are similar to the HCs except that fluorine
moieties are on the carbon backbone instead of hydrogens; and several
miscellaneous liquified propellants such as dimethyl ether and ethanol.
Compressed gases such as carbon dioxide, nitrogen and nitrous oxide may
also provide possible solutions. Propellant systems which use HCFCs are
believed to only be temporary solutions because the ozone depleting
potential of these compounds may still be a problem. The prior art is
replete with examples of propellant systems which employ the above-noted
types of compounds; however, few propellant systems have been discovered
which are suitable alternatives to the use of chlorofluorocarbons in MDIs.
In the European Patent Application 0,372,777 of Riker Laboratories
(hereinafter EP application), there are disclosed several self-propelling
aerosol formulations which may be used in MDIs and which may be free from
chlorofluorocarbons. The formulations discussed in the EP application
comprise a medicament, 1,1,1,2-tetrafluoroethane (HFC-134a), a surface
active agent, and an adjuvant compound having a higher polarity than
1,1,1,2-tetrafluoroethane. According to the EP application, the presence
of an adjuvant compound of higher polarity than HFC-134a is a critical
feature of the preparation of a stable, effective aerosol formulation and
states that without a higher polarity adjuvant compound, HFC-134a would be
an unsuitable propellant system for use in an MDI. The EP application
states further that the preferred solubility parameter, which is somewhat
dependent on propellant polarity, ranges between 6.5 and 7.8
(cal/cm.sup.3).sup.1/2 and mixtures having a solubility parameter below
6.0 (cal/cm.sup.3).sup.1/2 would be unacceptable. Vapor pressure is
reported to preferably range between 40 and 90 psig and density is
reported to preferably range between 1.0 and 1.5 g/cm.sup.3. The EP
application states that the preferred ratio of HFC-134a:higher polarity
adjuvant compound ranges between 85:15 and 95:5.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide propellant
formulations for use in MDIs which have reduced or no chlorofluorocarbon
content.
It is another object of this invention to provide propellant formulations
for use in MDIs which are compatible with the elastomer seals that are
positioned at the juncture of the pressurized container and the valve
actuator.
It is another object of the present invention to provide formulations for
use in MDIs which include a drug and a surfactant suspended in HFC-134a
alone or in combination with other compounds such as perfluoropentane,
propane, butane, and isobutane.
It is yet another object of the present invention to provide formulations
for use in MDIs which primarily use hydrocarbon blends as the propellant.
According to the invention, experiments were conducted to reformulate a
typical MDI product to reduce or eliminate the use of chlorofluorocarbons.
In the experiments, micronized albuterol was used as the drug product and
oleic acid was used as the surfactant, although those skilled in the art
will recognize that the medicament and surfactant and their respective
concentrations may be chosen and varied to suit the objective of drug
deliver to the lungs of the patient. The ideal alternative propellant will
satisfy the following criteria: (1) The propellant blend should consist of
a single liquid phase at room temperature, (2) the surfactant (oleic acid)
should dissolve in the propellant blend, (3) the micronized drug
(albuterol) should be easily dispersible in the propellant blend with the
aid of the surfactant (oleic acid), (4) the vapor pressure should range
between 50 to 110 psia at 21.degree. C., (5) the formulation may contain a
low vapor pressure component to facilitate slurry preparation which is
typically used for packaging MDI products, (6) the aerosolized drug
(albuterol) particle size following spraying should be as small as
possible to maximize penetration into the lung, and (7) the propellant
blend should be compatible with existing valve components, elastomer seals
and packaging equipment. The flammability of the propellant was considered
for safety reasons, but is not considered to preclude use in an MDI as
evidenced by the common use of flammable propellants in the hairspray and
breath freshener industry.
The types of propellants examined included chlorofluorocarbons (CFC-11, 12
and 114), hydrochlorofluorocarbons (CCl.sub.2 HCF.sub.3 which is commonly
called HCFC-123), hydrofluorocarbons (HFC-134a), hydrocarbons (propane,
n-butane and isobutane), fluorocarbons (perfluoropentane), dimethyl ether
and ethanol. The CFC, HCFC and dimethyl ether propellants are commercially
available from the E.I. DuPont De Nemours company of Delaware. The
hydrocarbon propellants are commercially available from Phillips 66
Chemical company of Oklahoma. In the experiments, two component propellant
blends and HFC-134a alone were evaluated in the presence of micronized
albuterol and oleic acid. The results of the experiments reported herein
include vapor pressure (which ranged between 65-110 psia at 23.degree.
C.), albuterol dispersion characteristics, oleic acid solubility, the
number of liquid phases, density (which ranged between 0.39 and 1.34 g/ml
at 21.degree. C.), flame extension (which varied from 50 cm to
non-flammable), product weight loss per actuation (which ranged between
33-94 mg per actuation), and the potentially respirable fraction (which
ranged between 22-39% of output less than or equal to 11.2 .mu.m in
aerodynamic diameter).
BRIEF DESCRIPTION OF THE TABLES
The foregoing and other objects, aspects and advantages will be better
understood from the following detailed description of a preferred
embodiment of the invention with reference to the tables, in which:
Table 1 shows the weight of propellant used in several test formulations,
these formulations also being referred to in Table 2 through 6;
Table 2 shows the density of several test formulations and the visual
characterization of the albuterol and oleic acid components in the
formulations;
Table 3 shows the calculated and measured vapor pressures of several test
formulations;
Table 4 shows the molecular weight, vapor pressure, and density of the high
pressure and the low pressure propellants used in the propellant blends;
Table 5 shows the observed flame extension for several test formulations
sprayed towards an open flame;
Table 6 shows average shot weight per actuation at two different times for
several test formulations which demonstrates the reproducibility of valve
metering for the formulations;
Table 7 shows the distribution of sprayed albuterol as determined by
cascade impaction for the formulations;
Table 8 shows the weight gain of particular elastomer seals after 24 hours
of immersion in liquified propellants; and
Table 9 shows the nitrile elastomer swelling after 24 hours of immersion in
liquified propellants.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
Various experiments have been performed with several different test
formulations in order to determine acceptable propellant systems which
might be utilized in MDIs. The primary focus of the experiments was to
determine suitable alternatives to the chlorofluorocarbon propellants that
are presently in widespread use.
With reference to the drawings and, more particularly to Table 1, several
different test formulations were prepared and, with the exception of the
test formulation containing HFC-134a as the sole propellant (shown at the
top of Table 1), each of these test formulations contained high and low
pressure propellant components. The composition of all propellant blends
was calculated with the assumption that all propellants behaved as ideal
liquids which obey Raoult's law. Using this assumption, the objective was
to produce binary (two component) propellant blends comprised of one high
and one low pressure propellant with a calculated vapor pressure near 67
psia at 21.degree. C., which is the calculated vapor pressure of the 72%
w/w CFC-12 and 28% w/w CFC-11 blend used in several commercial MDI
formulations. It should be understood that propellant blends with three or
more components could similarly be prepared. Each test formulation was
prepared by adding 32.3.+-.0.2 mg of micronized albuterol and 20.2.+-.0.3
mg of oleic acid to 10 ml of each propellant blend in a pressure resistant
aerosol container. The aerosol containers were fitted with both continuous
and metering valves using commercially available Pamasol small scale
aerosol packaging equipment available from Pfaffikon of Switzerland.
Suitable containers, valves and gaskets are commercially available from
the Bespak company of North Carolina. The formulations were shaken and
ultrasonicated for the purpose of dissolving the oleic acid and dispersing
the albuterol. In addition to reporting the actual weight of each
propellant in g/10 ml and the weight percentage of each propellant for
each test formulation, Table 1 also reports the calculated blend density
for the propellant compositions assuming ideal mixing. The vapor pressure,
density, and molecular weight reported by the supplier of each propellant
was used as the basis for all calculations.
In the following experiments discussed in conjunction with Table 2-7, the
response of the test formulations containing HFC-134a alone or HFC-134a in
combination with perfluoropentane and isobutane are deemed to be
particularly relevant. Rather than having a more polar adjuvant compound
act in combination with HFC-134a as is stated to be critical in EP
application 0,372,777 to aid in dissolving the surface acting agent and in
dispersing the medicament, these formulations either have no adjuvant
compound, as is the case where HFC-134a is utilized alone as the
propellant, or have a low pressure component which has a solubility
parameter that is less than HFC-134a (e.g., HFC-134a has a solubility
parameter of 6.6 (cal/cm.sup.3).sup.1/2 while perfluoropentane has a
solubility parameter of 5.66 (cal/cm.sup.3).sup.1/2 and isobutane has a
solubility parameter of 6.17 (cal/cm.sup.3).sup.1/2 In addition, the
hydrocarbon based blends were also found to have particularly promising
characteristics for use in MDIs.
Table 2 the calculated and measured blend densities for all the test
formulations as well as the results of a visual examination of each test
formulation which was made within two days of preparing the aerosol unit.
The calculated blend density at 21.degree. C. was determined, as stated
above, assuming ideal mixing and using the actual weight and reported
densities of propellants in the blend indicated in Table 1. The measured
blend density at 21.degree. C. for the propellant blends was determined
from blank formulations which did not contain albuterol or oleic acid
using a densitometer. It should be understood that many solid drugs have
densities which are similar in magnitude to albuterol.
While density is not dispositive of the utility of a propellant blend,
mismatches between drug and propellant density can result in poor
suspension stability. In the DME/isobutane (density=0.61 g/ml) and
HFC-134a/perfluoropentane (density=1.41 g/ml) blends, rapid sinking and
floating, respectively, resulted. If albuterol floats to the propellant
surface due to a mismatch in density, a lower than expected dose is likely
to be released during the first actuation following a period of
quiescence. Surprisingly, albuterol sank to the bottom of the aerosol
container relatively slowly in formulations containing the hydrocarbon
propellant blends (which have relatively low densities). This property is
highly desirable for MDI applications and might be the result of a high
degree of particulate deaggregation, since small, individual particles are
known to sediment more slowly than larger aggregates. The formulation
which utilizes HFC-134a as the sole propellant and other HFC-134a based
blends, which have calculated densities ranging between 1.2 and 1.4 g/ml,
also had relatively stable suspensions.
In Table 2, albuterol which is described as "dispersed" easily produced a
visually homogeneous, opaque suspension on gentle shaking, while that
described as "aggregated" produced one or more large clumps suspended in
liquified propellant or adhered to the glass container. While not
specifically shown in Table 2, albuterol was relatively difficult to
deaggregate in CFC based formulations, but was very easy to deaggregate in
hydrocarbon based systems. In most hydrocarbon based formulations, the
albuterol spontaneously dispersed. The observed ease of albuterol
deaggregation in the hydrocarbon based formulations makes hydrocarbons
attractive alternatives to CFCs because shorter mixing times or the
complete absence of a need for homogenization would reduce manufacturing
costs and complexity. The method of MDI preparation used in these
investigations did not permit mechanical deaggregation of the micronized
albuterol in the liquified propellant (i.e., there was no direct contact
between a homogenizer head and aggregated particles of albuterol). In
place of the high shear mixers and homogenizers which are commonly used in
commercial filling operations, vigorous shaking and ultrasonication of
individually filled MDIs was employed in order to conserve propellant.
Despite these less forceful methods of mixing, in most cases a product was
produced that was judged by visual inspection to be dispersed and
deaggregated. In view of the above, it is possible that some formulations
reported in Table 2 which are identified as "aggregated" could have
benefitted from a dispersion technique that involved mechanical
deaggregation of albuterol aggregates.
In most of the test formulations, oleic acid was a viable surfactant and
dissolved completely at ambient temperature. The concentration of oleic
acid used in these studies (20 mg/10 ml or 0.2% weight in volume (w/v))
represents a high surfactant concentration compared to the concentration
used in several commercially available MDI products. Therefore, some of
the formulations identified as containing "undissolved" oleic acid may
still be useful in formulations which require reduced surfactant levels.
For example, in the formulation containing HFC-134a as the sole
propellant, oleic acid was only partly dissolved after shaking; however,
the large amount of oleic acid used in the experiments may not actually be
required in a typical MDI application and thus a suitable formulation in
HFC-134a alone would simply employ a lower concentration of entirely
dissolved oleic acid. In addition, other surfactants utilized in
commercial MDIs (e.g., sorbitan trioleate and soya lecithin), are known to
exhibit different solubility characteristics and may be suitable for use
with propellant blends in which oleic acid failed to dissolve.
All the propellant blends investigated displayed a single liquid phase at
ambient temperature which is a very important characteristic of any
propellant system which will be used in a metered dose inhaler environment
(patients use MDIs at room temperature). Most of the propellant blends
also remained as a single phase on cooling with dry ice/methanol; however,
the dimethyl ether (DME)/perfluoropentane blend separated into two liquid
phases when cooled in dry ice/methanol. Separation into two liquid phases
at low temperature would severely limit the utility of such a blend in a
cold filling operation, although the same blend may be amenable to
pressure filling.
Table 3 shows the calculated vapor pressure of the test formulations at
21.degree. C. where the calculations were made assuming ideal behavior,
and the measured vapor pressure at 23.degree. C. for the test formulations
(vapor pressure was measured using a calibrated gauge). Many of the
propellant blends investigated yielded vapor pressures close to the
expected value (65-85 psia at 23.degree. C.). Hence, the vapor pressure
experiment demonstrates that it is possible to achieve vapor pressures
similar to those encountered in current CFC based MDIs using alternative
propellants. In most cases the measured pressure exceeded the calculated
pressure. The most striking differences between calculated and measured
vapor pressures were observed in blends containing HFC-134a and a
hydrocarbon propellant wherein the formulations showed a vapor pressure
more than 40% higher than expected. The 2.degree. C. temperature
difference between the calculated pressure and the measured pressure
cannot account for this large variance. In addition, the propane and DME
blends mixed with the low pressure perfluoropentane component also showed
a vapor pressure approximately 30% higher than expected. Large pressure
differences such as these are indicative of a positive deviation from
Raoult's law and are probably indicative of little intermolecular bonding
between dissimilar propellant molecules.
Table 4, with reference back to Table 3, shows that with the exception of
the formulation containing only HFC-134a as the propellant, all MDIs
contained a low pressure component which would facilitate slurry
formation. High pressure propellants are herein defined as those
exhibiting vapor pressures greater than 67 psia at 21.degree. C. and low
pressure propellants are herein defined as those exhibiting vapor
pressures less than 67 psia at 21.degree. C. (or 25.degree. C. as in the
case of perfluoropentane). The molecular weight, vapor pressure and
density information reported in Table 4 were obtained from the propellant
suppliers and the values are quoted at 21.degree. C. unless 25.degree. C.
appears in parenthesis. Because of the presence of the low pressure
component, it is likely that all test formulations, except the formulation
containing HFC-134a alone, could be filled using conventional cold or
pressure filling technology. To fill products containing HFC-134a, which
has a boiling point of -26.degree. C., as the sole propellant, may require
a different approach, such as pressure filling the premixed suspension in
a single stage process.
Table 5 shows the observed flame extension for the test formulations. Flame
extension was measured by firing each MDI horizontally from 10 cm towards
a 2 cm propane flame in a draught free enclosure. The distance the flame
extended from the actuator orifice was determined from a linear scale
mounted in the plane of the flume. Formulations containing strongly
aggregated albuterol, or in which oleic acid remained undissolved were
tested using continuous valves since these valves are less prone to
blockage and the remaining formulations were tested using 63 .mu.l
metering valves. Except for the formulation containing 1% w/w ethanol in
HFC-134a, all formulations containing a flammable component produced a
measurable flame extension when sprayed into a propane flame. The flame
was of extremely short duration in most cases, although formulations
containing n-butane showed a tendency to burn slightly longer and had a
small flame retreating to the actuator nozzle. Propellants containing
propane tended to yield the longest flame extension. MDI gassing using
flammable propellants is more difficult than using non-flammable CFCs, but
is technically feasible.
Table 6 shows the mean weight loss per actuation one hour and twenty four
hours after filling each unit with a test formulation. Only test
formulations in which albuterol was judged to be dispersed, and oleic acid
dissolved are reported in Table 6-7. Following priming (test firing after
filling to fill the metering chamber with propellant), each MDI was
weighed before and after ten actuations and the average weight loss per
actuation was determined. The expected shot weight for those units which
were fitted with a 63 .mu.l metering valve was determined by multiplying
the measured blend density (from Table 1 and 2) of the test formulation by
63/1000. In many of the formulations (e.g., the HFC-134a/n-butane
formulation), the observed shot weight was close to the expected value
based on measured propellant density and valve metering volume. Moreover,
the observed shot weight in many formulations did not alter appreciably
over the 24 hour storage period.
Table 7 shows the deposition results of albuterol sprayed into a cascade
impactor for several aerosol units containing the test formulations. Each
unit was fitted into the aerosol inlet port of an evaporation chamber
located atop a calibrated cascade impactor (specifically, the Delron DCI-6
of Powell, Ohio), through which air was drawn at 12.45 liters/min, and
discharged 10 times with shaking between each actuation. The procedure has
been fully described in "Comparison of output particle size distributions
from pressurized aerosols formulated as solutions and suspensions",
Richard N. Dalby and Peter R. Byron, Pharm. Res., 5, 36-39 (1988), and
that article is hereby incorporated by reference. The actuator,
evaporation chamber, each slide and the terminal filter of the impactor
were washed with 50% volume in volume (v/v) aqueous methanol and analyzed
for drug by high performance liquid chromatography (HPLC). Albuterol
deposition in the actuator accounted for approximately 19% (standard
deviation=4%) of the total emitted dose from all formulations. Deposition
in the evaporation chamber was more variable, accounting for approximately
51% (standard deviation=6%) of the total emitted dose from all
formulations. Evaporation chamber deposition is probably attributable to
particles with aerodynamic diameters greater than 11.2 .mu.m, and is
likely to be indicative of particles or droplets which would impact in the
mouth or oropharynx following inhalation. The percentage of the emitted
dose reaching the cascade impactor following spraying of reformulated MDIs
was compared to a control formulation (identified in Table 7 as
"CFC-11/CFC-12") which contained albuterol and oleic acid in a 72% w/w CFC
12 and 28% w/w CFC-11 (a mixture commonly used in conventional CFC based
MDIs). In comparison to this control, several reformulated MDIs produced
more, or an equivalent fractional deposition within the impactor, where at
least a proportion of the particles are expected to be respirable if
inhaled. Particles within the impactor have an aerodynamic diameter less
than 11.2 .mu.m, which is similar to that claimed for Apparatus 1 in the
British Pharmacopoeia where particles recovered from the second stage have
an aerodynamic diameter of less than about 10 .mu.m (see, British
Pharmacopoeia, p. 875, appendix XVII C, A204-A207 (1988)).
Referring back to Table 6, the mean shot weight was observed to decrease
markedly over the 24 hour storage period for some formulations, and the
valve became stiff or failed to fire in certain aerosol units (e.g.,
CFC-12/isobutane, CFC-12/HCFC-23, and propane/HCFC-123). This stiffness
resulted despite the fact that 0.2% weight in volume (w/v) oleic acid was
completely dissolved in the propellant blend test formulations and should
have provided adequate lubrication. Stiffness in the operation of the
valve actuator may cause less than the expected volume of aerosol to be
delivered, and this would account for the corresponding decrease in mean
shot weight over the 24 hour time period. The inventors determined that
stiff operation of the valve actuator could be the result of the
propellants in the test formulations causing swelling of the nitrile seats
positioned at the juncture of the valve actuator and pressurized aerosol
container (nitrile seats were used with all the test aerosol units
discussed above in conjunction with Table 1-7).
Table 8 shows the weight gain of several elastomeric materials following
immersion in a liquified propellant for 24 hours. Low density polyethylene
(LDP), nitrile, chlorobutyl, black and white buna, butyl and neoprene are
all commercially used gasket materials for aerosol containers. One
preweighed seal of each type of elastomer was placed in a 20 ml aerosol
bottle which was subsequently sealed using a continuous valve, and filled
with liquified propellant through the valve. After 24 hours, the valve was
removed and the seals reweighed as rapidly as possible. All propellants
caused some degree of swelling in all elastomers tested, with the
exception of perfluoropentane. After approximately one month the seals
were weighed again. With the exception of nitrile rubber in dimethyl
ether, which decreased in weight by 5%, all other elastomers returned to
100.+-.2% of their initial weight after one month standing in air at
ambient temperature.
Table 8 shows that all the elastomeric compounds tested, except
chloro-butyl and butyl rubbers, showed only very limited swelling after
twenty four hours of exposure to the alkane propellants (e.g., propane,
n-butane, and isobutane). HFC-134a caused limited swelling of the LDP,
chlorobutyl, butyl and neoprene gaskets, but caused a significant amount
of swelling of the nitrile and black and white buna gaskets. Nitrile
rubber was also found to be particularly affected by HCFC-123, which
caused an approximately 400% increase in gasket weight. HCFC-123 also
induced swelling of a similar magnitude in black and white buna gaskets.
The nitrile rubber gasket which was immersed in dimethyl ether gave rise
to a brown supernatant liquid after one month of standing in air at
ambient temperature which is indicative of limited dissolution or leaching
of significant amounts of extractables.
Table 9 shows the results of a second experiment where preweighed and
premeasured nitrile elastomer gaskets placed in an aerosol bottle filled
with a liquified propellant, as described above in conjunction with Table
8, and removed and rapidly weighed and measured after a twenty four hour
period. Nitrile swelling and weight increase for gaskets placed in the
alkane propellants was only slight and was of the same order of magnitude
as that found with CFC-12 and CFC-114. The nitrile gaskets exposed to
CFC-11, dimethyl ether and HCFC-123 all experienced an increase in length
and a substantial percentage increase in weight. The nitrile gasket
exposed to HFC-134a exhibited modest increases in length and weight. The
nitrile gasket exposed to perfluoropentane had a slight decrease in length
and no appreciable change in weight.
Some elastomer swelling is desirable for the MDI environment since the
gasket provides a seal between the aerosol container and the valve
actuator. Therefore, using perfluoropentane alone as a propellant in an
MDI may not produce satisfactory results since, as is shown in Table 8 and
9, no appreciable swelling occurred for any of the several elastomer
gaskets examined. Too much elastomer swelling, as is the case for example
when nitrile or black or white buna gaskets are exposed to either HCFC-123
or dimethyl ether (see Table 8 an 9), is undesirable since this leads to
stiff operation of the valve actuator (as discussed above in conjunction
with Table 7). The results in Table 8 and 9 show that the alkane and CFC
propellants produce optimum results with a wide variety of elastomer
materials. However, it should be understood that optimum elastomer
swelling results can be achieved by combining propellants into blends.
For example, in the experiments reported in Table 2-7, aerosol containers
with nitrile gaskets were utilized. Table 6 shows that aerosol units
filled with HFC-134a/iso-butane and HFC-134a/n-butane propellant blends
had no appreciable decline in the mean shot weight per actuation twenty
four hours after assembling the aerosol units and neither of these aerosol
units experienced stiff operation of the valve actuator. Yet, Table 8 and
9 show that nitrile gasket exposure to HFC-134a causes noticeable swelling
within twenty four hours. Hence, the combination of an alkane propellant
with HFC-134a may allow a nitrile gasket to be used in the MDI environment
when HFC-134a is the high pressure propellant of choice. The inventors
consider similar combinations of propellants, including combinations of
three or more propellants, to achieve optimum elastomer swelling results
to be within the scope of this invention. The propellants chosen for any
particular blend will depend upon the type of elastomer seal used.
In the experiments, albuterol was used as the medicament; however, it
should be understood that many other medicaments could be used with the
inventive propellant blends. Albuterol is a white crystalline drug present
as a micronized suspension and is typical of many other drugs delivered by
MDIs. For pharmaceutical purposes, the particle size of the powder is
preferably no greater than 100 microns in diameter, since larger particles
may clog the metering valve or orifice of the container. Preferably, the
particle size should be less than 10 microns in diameter. The
concentration of medicament depends upon the desired dosage, but will
generally be in the range 0.001 to 5% by weight. In addition, in the
experiments oleic acid was used as the surfactant for dispersing the
albuterol; however it should be understood that many different surfactants
could be employed with the inventive propellant blends. As recently
reported in Dalby et al., "CFC Propellant Substitution: P-134a as a
Potential Replacement for P-12 in MDIs", Pharm. Tech., March, 1990, pages
26 to 33, the percentage composition of each propellant constituent in a
propellant blend required for completely dissolving a surfactant varies
with the type of surfactant used and the weight percentage of the
surfactant mixed into the propellant blend. Hence, the MDI application
will influence the choice of surfactant and the final concentrations of
propellants utilized. In most MDI formulations, surfactants will be
present in amounts not exceeding five percent of the total formulation and
are usually present in the weight ratio of 1:100 to 10:1 surface active
agent:drug(s), but the surface active agent may exceed this weight ratio
in cases where the drug concentration in the formulation is very low and
be reduced below the ratio in certain cases where novel valve technology
which reduces the requirement for valve lubrication is employed.
While the invention has been described in terms of its preferred
embodiments wherein albuterol and oleic acid are either suspended in a
formulation comprised of HFC-134a alone or HFC-134a blended with another
propellant compound or suspended in a formulation comprised of a binary
hydrocarbon blend, those skilled in the art will recognize that the
medicament and surfactant chosen, the percentages of the propellant
constituents in the HFC-134a and hydrocarbon blends, and the number of
propellants used in the blend (e.g., binary, tertiary, and quaternary
blends) can be varied within the spirit and scope of the appended claims.
TABLE 1
______________________________________
Composi- Composi-
High tion.sup.a tion.sup.a
Blend.sup.b
Pressure
% g/10 Low Pressure
% g/10 Density
Component
w/w ml.sup.c
Component w/w ml.sup.c
(g/ml)
______________________________________
HFC-134a
100 12.2 None 0 0 1.22
HFC-134a
99 12.1 Ethanol (95%)
1 0.1 1.22
HFC-134a
56 5.2 iso-Butane
44 4.1 0.93
HFC-134a
68 6.9 n-Butane 32 3.3 1.01
HFC-134a
58 7.7 CFC-11 42 5.7 1.33
HFC-134a
56 7.5 HCFC-123 44 5.8 1.33
HFC-134a
45 6.1 CFC-114 55 7.5 1.36
HFC-134a
40 5.8 Perfluoro-
60 8.8 1.45
pentane
CFC-12 71 7.8 iso-Butane
29 3.3 1.10
CFC-12 80 9.4 n-Butane 20 2.4 1.18
CFC-12 72 9.9 CFC-11 28 3.8 1.37
CFC-12 71 9.7 HCFC-123 29 4.0 1.37
CFC-12 60 8.4 CFC-114 40 5.5 1.38
CFC-12 55 8.0 Perfluoro-
45 6.5 1.45
pentane
Propane 22 1.2 iso-Butane
78 4.3 0.55
Propane 32 1.8 n-Butane 68 3.8 0.56
Propane 23 2.9 CFC-11 77 9.6 1.26
Propane 22 2.8 HCFC-123 78 9.8 1.25
Propane 15 2.0 CFC-114 85 11.2 1.32
Propane 13 1.9 Perfluoro-
87 12.8 1.46
pentane
DME 60 3.7 iso-butane
40 2.5 0.62
DME 72 4.6 n-butane 28 1.8 0.64
DME 62 6.0 CFC-11 38 3.7 0.98
DME 60 5.9 HCFC-123 40 3.9 0.98
DME 49 5.3 CFC-114 51 5.5 1.07
DME 44 5.2 Perfluoro-
56 6.7 1.19
pentane
______________________________________
.sup.a The composition of all propellant blends (except the first two) wa
calculated assuming all propellants behaved as ideal liquids and,
therefore, obey Raoults law. Using this assumption it is possible to
produce binary propellant blends of one low and one high pressure
propellant with calculated vapor pressures of 67 psia at 21.degree. C.,
the calculated vapor pressure of 72% w/w CFC12 and 28% w/w CFC11.
.sup.b Density was calculated assuming ideal mixing.
.sup.c Actual propellant composition deviated from the nominal compositio
by an average of 0.4% and 6.1% (by weight) for the low and high pressure
components, respectively.
TABLE 2
______________________________________
Density g/ml Visual Characterization
Formulation
Calculated.sup.a
Measured.sup.b
Albuterol
Oleic Acid
______________________________________
HFC-134a 1.22 1.22 Floats/ Part
Dispersed
Dissolved
HFC-134a/
1.22 1.21 Floats/ Dissolved
Ethanol Aggregated
HFC-134a/
0.96 0.76 Sinks/ Undis-
iso-Butane.sup.c Aggregated
solved
HFC-134a/
1.02 0.86 Sinks/ Dissolved
n-Butane.sup.c Dispersed
HFC-134a/
1.33 1.31 Floats/ Dissolved
CFC-11 Dispersed
HFC-134a/
1.32 1.32 Floats/ Dissolved
HCFC-123 Aggregated
HFC-134a/
1.35 1.33 Adhered to
Undis-
CFC-114 OA solved
HFC-134a/
1.44 1.41 Floats/ Undis-
Perfluoro- Aggregated
solved
pentane
CFC-12/ 1.10 1.00 Sinks/ Dissolved
iso-Butane Dispersed
CFC-12/ 1.17 0.83 Sinks/ Dissolved
n-Butane Dispersed
CFC-12/ 1.37 1.27 Floats/ Dissolved
CFC-11 Dispersed
CFC-12/ 1.37 1.43 Floats/ Dissolved
HCFC-123 Dispersed
CFC-12/ 1.38 1.36 Floats/ Dissolved
CFC-114 Aggregated
CFC-12/ 1.45 1.50 Floats/ Undis-
Perfluoro- Dispersed
solved
pentane
Propane/ 0.55 0.54 Sinks/ Dissolved
iso-Butane Dispersed
Propane/ 0.56 0.55 Sinks/ Dissolved
n-Butane Dispersed
Propane/ 1.25 1.03 Sinks/ Dissolved
CFC-11 Dispersed
Propane/ 1.25 1.04 Sinks/ Dissolved
HCFC-123 Dispersed
Propane/ 1.30 1.13 Suspended/
Undis-
CFC-114 Dispersed
solved
Propane/ 1.47 1.21 Floats/ Undis-
Perfluoro- Dispersed
solved
pentane.sup.c
DME/iso- 0.62 0.61 Sinks/ Dissolved
butane Dispersed
DME/n- 0.64 0.63 Sinks/ Dissolved
butane Dispersed
DME/ 0.98 0.85 Sinks/ Dissolved
CFC-11 Dispersed
DME/ 0.86 NP NP
HCFC-123
DME/ 1.07 0.92 Sinks/ Dissolved
CFC-114 Dispersed
DME/ 1.19 0.80 Sinks/ Dissolved
Perfluoro- Aggregated
pentane.sup.c
______________________________________
.sup.a Density at 21.degree. C. was calculated from the actual weight of
propellant used to prepare each blend, assuming ideal mixing.
.sup.b Measured at 21.degree. C.
.sup.c Propellant separated into two liquid phases when cooled in dry
ice/methanol.
TABLE 3
______________________________________
Vapor Pressure (psia)
Formulation Calculated.sup.a
Measured.sup.b
______________________________________
HFC-134a 95.7 100
HFC-134a/Ethanol 95.7 105
HFC-134a/iso-Butane
68.8 110
HFC-134a/n-Butane
66.9 95
HFC-134a/CFC-11 66.9 80
HFC-134a/HCFC-123
69.8 65
HFC-134a/CFC-114 67.8 80
HFC-134a/Perfluoro-
69.1 80
pentane
CFC-12/iso-Butane
66.5 75
CFC-12/n-Butane 66.2 70
CFC-12/CFC-11 67.2 70
CFC-12/HCFC-123 66.5 70
CFC-12/CFC-114 66.7 80
CFC-12/Perfluoro-
67.2 65
pentane
Propane/iso-Butane
67.1 70
Propane/n-Butane 66.2 65
Propane/CFC-11 71.4 80
Propane/HCFC-123 66.2 ND.sup.c
Propane/CFC-114 70.3 80
Propane/Perfluoro-
65.9 95
pentane
DME/iso-butane 66.7 80
DME/n-butane 67.4 75
DME/CFC-11 66.9 65
DME/HCFC-123 NP.sup.d NP
DME/CFC-114 66.5 70
DME/Perfluoro- 66.3 85
pentane
______________________________________
.sup.a Vapor pressure at 21.degree. C. was calculated from the actual
weight of propellant used to prepare each blend, assuming ideal behavior.
.sup.b Pressures are reported to the nearest 5 psi at 23.degree. C.
.sup.c ND = not determined due to valve blockage.
.sup.d NP = not prepared due to valve blockage.
TABLE 4
______________________________________
Vapor.sup.a
Den-
Mo- pressure
sity.sup.a
lecular psia g/ml
Propellant
Formula Weight (21.degree. C.)
(21.degree. C.)
______________________________________
High Pressure Propellants.sup.h (>67 psia)
HFC-134a.sup.c
CH.sub.2 F--CF.sub.3
102.0 95.7 1.224
Propane.sup.d, f
CH.sub.3 --CH.sub.2 --CH.sub.2
44.1 122.7 0.509
Dimethyl-
CH.sub.3 --O--CH.sub.3
46.1 77.7 0.661
ether
(DME).sup.d, f
CFC-12.sup.c
CCl.sub.2 F.sub.2
120.9 84.9 1.325
Low Pressure Propellants (<67 psia)
HCFC-123.degree.
CF.sub.3 --CHCl.sub.2
152.9 11.0 1.465
(25.degree. C.)
n-Butane.sup.d, f
CH.sub.3 --(CH.sub.2).sub.2 --CH.sub.3
58.1 31.7 0.585
iso-Bu- CH(CH.sub.3).sub.3
58.1 45.7 0.564
tane.sup.d, f
CFC-11.sup.c
CCl.sub.3 F 137.4 13.3 1.485
CFC-114.sup.c
CClF.sub.2 --CClF.sub.2
170.9 27.3 1.468
Perfluoro-
CF.sub.3 --(CF.sub.2).sub.3 --CF.sub.3
288 12.5 1.604
Pentane.sup.e (25.degree. C.)
(25.degree. C.)
______________________________________
.sup.a Vapor pressure and density information was obtained from
appropriate propellant supplier. Values are quoted at 21.degree. C. unles
25.degree. C. appears in parenthesis.
.sup.b High pressure propellants in this paper are defined as those
exhibiting vapor pressure >67 psia at 21.degree. C.
.sup.c Du Pont, Wilmington, DE.
.sup.d Phillips 66 Co., Bartlesville, OK.
.sup.e ISC Chemicals, Avonmouth, United Kingdom.
.sup.f Flammable at certain concentrations in air.
TABLE 5
______________________________________
Formulation Flame Extension (cm)
______________________________________
HFC-134a Non-flammable
HFC-134a/Ethanol Non-flammable
HFC-134a/iso-Butane
20
HFC-134a/n-Butane 30
HFC-134a/CFC-11 Non-flammable
HFC-134a/HCFC-123 Non-flammable
HFC-134a/CFC-114 Non-flammable
HFC-134a/Perfluoro-
Non-flammable
pentane
CFC-12/iso-Butane 20
CFC-12/n-Butane 20
CFC-12/CFC-11 Non-flammable
CFC-12/HCFC-123 Non-flammable
CFC-12/CFC-114 Non-flammable
CFC-12/Perfluoro- Non-flammable
pentane
Propane/iso-Butane 50
Propane/n-Butane 40
Propane/CFC-11 20
Propane/HCFC-123 20
Propane/CFC-114 50
Propane/Perfluoro- 40
pentane
DME/iso-butane 30
DME/n-butane 30
DME/CFC-11 20
DME/HCFC-123 NP.sup.a
DME/CFC-114 20
DME/Perfluoro- Non-flammable/15.sup.b
pentane
______________________________________
.sup.a NP = not prepared due to valve blockage.
.sup.b During six repeat extension tests this formulation extinguished th
propane torch twice, appeared nonflammable once and showed a flame
extension of 15 cm three times.
TABLE 6
______________________________________
Mean Shot Weight/
Actuation (mg, n = 10)
1 Hour 24 Hours
Post Post
Crimping Crimping Expected.sup.a
of Metering
of Metering Shot Wt.
Formulation Valve Valve (mg)
______________________________________
HFC-134a 81.sup.b 76 77.sup.c
HFC-134a/iso-Butane
51 50 48
HFC-134a/n-Butane
53 50 54
HFC-134a/CFC-11
79 75 83
CFC-12/iso-Butane
57 Failed to Fire
63
CFC-12/n-Butane
70 65 52
CFC-12/CFC-11
94 82 80
CFC-12/HCFC-123
80 Stiff
59 90
Propane/iso-Butane
34 32 34
Propane/n-Butane
33 33 35
Propane/CFC-11
58 57 65
Propane/HCFC-123
57 Stiff
50 65
DME/iso-butane
35 37 38
DME/n-butane 38 37 40
DME/CFC-11 47 44 54
DME/CFC-114 55 54 58
DME/Perfluoro-
58 59 50
pentane
______________________________________
.sup.a Expected shot weight = Density .times. 63/1000. Where Density is
the measured propellant density, and 63 ul is the volume of the metering
valve.
.sup.b Valve operated smoothly and without unusual stiffness unless
otherwise noted.
.sup.c ND = not determined
TABLE 7
______________________________________
Percentage Deposition in
Evaporation
Formulation Actuator Chamber Impactor
______________________________________
HFC-134a 16 (2) 40 (5) 44 (6)
HFC-134a/n-Butane
21 (2).sup.a
51 (4) 27 (4)
HFC-134a/CFC-11
14 (1) 65 (4) 22 (3)
CFC-12/iso-Butane
18 (1) 48 (1) 33 (1)
CFC-12/n-Butane
17 (1) 55 (2) 28 (2)
CFC-12/CFC-11
20 (1) 55 (4) 26 (4)
CFC-12/HCFC-123
8.sup.b 57 34
Propane/iso-Butane
20 (2) 42 (4) 39 (4)
Propane/n-Butane
16 (3) 55 (1) 29 (1)
Propane/CFC-11
21 (1) 46 (2) 33 (1)
Propane/HCFC-123
22 (1) 45 (2) 34 (1)
DME/iso-butane
18 (1) 50 (2) 32 (2)
DME/n-butane 21 (1) 47 (2) 33 (2)
DME/CFC-11 23 (3) 50 (4) 27 (2)
DME/CFC-114 21 (0) 51 (1) 28 (1)
DME/Perfluoro-
18 (2) 46 (5) 36 (4)
pentane
______________________________________
.sup.a Mean of 3 replicates. Value in parenthesis represents 0.5 .times.
Range.
.sup.b MDI failed to fire after first cascade impaction experiment.
TABLE 8
__________________________________________________________________________
% of Initial Weight After 24 h Immersion in Propellant.sup.b
Propellant
LDP.sup.a
Nitrile
Black Buna
White Buna
Chlorobutyl
Butyl
Neoprene
__________________________________________________________________________
CFC-11
127 141 142 137 227 286 170
CFC-12
110 106 106 105 125 136 111
CFC-114
103 100 101 101 107 109 102
Propane
107 102 102 102 109 117 104
iso-Butane
107 101 101 101 120 129 106
n-Butane
107 102 102 102 123 141 107
HFC-134a
101 117 112 114 100 101 101
HCFC-123
109 414 457 398 145 158 136
DME 105 135 133 135 110 120 120
Perfluoro-
100 100 100 100 100 100 100
propane
__________________________________________________________________________
.sup.a LDP = low density polyethylene.
.sup.b 100 represents no weight gain.
TABLE 9
______________________________________
% Increase in % Increase in
Length of Nitrile
Weight of Nitrile
Elastomer After 24 h
Elastomer After 24 h
Propellant in Propellant in Propellant
______________________________________
CFC-11 10.7 40.1
CFC-12 3.9 5.6
CFC-114 4.0 0.8
HCFC-123 52.9 293.3
HFC-134a 8.0 16.5
Butane 3.4 2.2
Isobutane 3.8 1.1
Propane 2.4 5.3
Dimethylether
15.9 30.6
Perfluoropentane
-1.4 0.2
______________________________________
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